1-100992731-C-T

Variant names:

• chr1-100992731-C-T
• rs373947841
• NM_015958.3:c.540G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015958.3(DPH5):​c.540G>A​(p.Lys180Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000206 in 1,459,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DPH5 NM_015958.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 1 publications found

Genes affected

DPH5 (HGNC:24270): (diphthamide biosynthesis 5) This gene encodes a component of the diphthamide synthesis pathway. Diphthamide is a post-translationally modified histidine residue found only on translation elongation factor 2. It is conserved from archaebacteria to humans, and is targeted by diphtheria toxin and Pseudomonas exotoxin A to halt cellular protein synthesis. The yeast and Chinese hamster homologs of this protein catalyze the trimethylation of the histidine residue on elongation factor 2, resulting in a diphthine moiety that is subsequently amidated to yield diphthamide. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SLC30A7 (HGNC:19306): (solute carrier family 30 member 7) Zinc functions as a cofactor for numerous enzymes, nuclear factors, and hormones and as an intra- and intercellular signal ion. Members of the zinc transporter (ZNT)/SLC30 subfamily of the cation diffusion facilitator family, such as SLC30A7, permit cellular efflux of zinc (Seve et al., 2004 [PubMed 15154973]).[supplied by OMIM, Mar 2008]

SLC30A7 Gene-Disease associations (from GenCC):

• Joubert syndrome

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015958.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH5	NM_015958.3	MANE Select	c.540G>A	p.Lys180Lys	synonymous	Exon 7 of 8	NP_057042.2	Q9H2P9-1
	DPH5	NM_001077394.2		c.540G>A	p.Lys180Lys	synonymous	Exon 7 of 8	NP_001070862.1	Q9H2P9-1
	DPH5	NM_001077395.2		c.540G>A	p.Lys180Lys	synonymous	Exon 7 of 8	NP_001070863.1	Q9H2P9-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH5	ENST00000370109.8	TSL:1 MANE Select	c.540G>A	p.Lys180Lys	synonymous	Exon 7 of 8	ENSP00000359127.3	Q9H2P9-1
	DPH5	ENST00000427040.3	TSL:1	c.540G>A	p.Lys180Lys	synonymous	Exon 6 of 7	ENSP00000394364.3	Q9H2P9-1
	DPH5	ENST00000342173.11	TSL:1	c.540G>A	p.Lys180Lys	synonymous	Exon 7 of 8	ENSP00000339630.7	Q9H2P9-6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249028 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459578 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726146

African (AFR) AF: 0.0000598 AC: 2 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110372

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	9.4
DANN	Benign	0.68
PhyloP100		5.7
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373947841; hg19: chr1-101458287;